A demand for a technique of an effective and rapid preparation of very fine particles in regular size has been constantly required in various industrial fields. Such fine particles in regular size have many advantages, particularly among which good flowability and little deviation in particle interaction are very advantageous in industrial application. In medical field, the particle size of a therapeutic agent greatly affects to the dissolution rate, bioavailability, formulation and the like, and for example, the smaller the deviation in the interaction between the particles of a therapeutic agent is, the better the whole stability of the therapeutic agent becomes.
When the particle of a therapeutic agent is made into nanoscale size in medicinal products, following advantages may be obtained. First of all, in a drug having a small enteral absorption rate in oral administration, one having a smaller size can be absorbed more than one having a bigger size, thereby increasing the bioavailability of the therapeutic agent. Further, the dosage form of drugs can be varied, for instance a drug being possibly administered only via oral route can be administered by inhalation. In a controlled-release drug formulation, the release rate of a therapeutic agent is a very important factor. When the particle size of the therapeutic agent is formed to be in nanoscale, the particle size becomes relatively more uniform, thus the release rate can become more expectable, thereby being possible to provide more effective therapeutic agent.
In order to take various advantages of regular nanoparticles as described above, many attempts have been made to prepare an active ingredient as a nanoparticle. For this object, mechanical techniques such as crushing, grinding, milling and the like have been conventionally employed to make relatively large particles smaller. In the pharmaceutical industry, a method of milling a mass amount of drugs to the size range being suitable for the medicinal or pharmaceutical use with an air-jet mill has been commonly used. However, such mechanical process involves the risk of contamination and had a limitation on decreasing the particle size to about tens of micrometers.
U.S. Pat. No. 5,145,684 discloses a method for preparing particles of poorly water-soluble drugs in the size of hundreds of nanometers by wet milling the poorly water-soluble drugs in the presence of a surface modifier. This teclmique should be applied after a preparation of the drugs in the particle size of not more than 100 micrometer by using a conventional milling process. Generally in this method, the time taken for the preparation of particles having a targeted size range depends on the particular mechanical device used thereto. For example, when using a ball mill, processing times of up to 5 days or longer may be required, however, when using a high shear media mill, 1 day would be enough to provide particles of a desired size. However, in connection with the use of a high shear media mill, contamination associated with the high corrosion of grinding media and grinding vessel should be concerned. Further, a drying process such as spray or freeze drying should be conducted for getting powder form, because the resulted nanoparticles from the wet milling method are in liquid phase. During the drying process, coagulation of the particles is occurred due to interparticle attraction forces, hence it is substantially difficult to obtain a dispersion of particles in a nanometer scale by redispersing the resulted powder into a liquid. In order to solve such problem, U.S. Pat. No. 5,302,401 describes an anti-coagulating agent employed during lyophilization. Additionally, U.S. Pat. No. 6,592,903 B2 describes an invention comprising a stabilizer, a surfactant and an anti-coagulating agent used during a spray dry process. Further, US Patent No. 2003/0185869 A1 describes an application of a wet milling technique for some poorly soluble drugs, with using lysozyme as a surface stabilizer. However, such protein surface stabilizer used therein has many restrictions in a drying process, accordingly it only describes the preparation in liquid phase.
Other conventionally available methods include a recrystallization technique which provides fine particles of an active ingredient by changing the environment of a solution containing dissolved active ingredient to cause the precipitation or crystallization of solutes. The recrystallization technique can be practiced in two different ways: the one being comprised of dissolving a therapeutic agent in a suitable solvent and lowering the temperature, thereby changing the solubility of the therapeutic agent to precipitate particles; and the other being comprised of adding antisolvent to a solution containing dissolved therapeutic agent, thereby decreasing the solubility of the solute to precipitate particles. However, the recrystallization technique usually requires the use of toxic organic solvent and often causes flocculation or coagulation of the particles during a drying process in wet condition, following after the filtration of the precipitated particles. As a result, the final particles may be irregular in their size.
US Patent No. 2003/0104068 A 1 discloses a method for preparing fine particles comprising: dissolving polymers into an organic solvent; dissolving or dispersing a proteineous drug thereto; then rapidly cooling the solution to ultra-low temperature for solidification; and lyophilizing the resulted product to provide a fine powder. In this case, however, there are concerns for the denaturation of a proteineous drug by the contact with an organic solvent and the process economy owing to the rapid cooling and lyophilizing process.
Other techniques for reducing particle size include emulsification. The emulsifying method is commonly used in cosmetic field, which comprises melting poorly water soluble substances with heat or dissolving them in an organic solvent, and then adding the melted or dissolved substances to an aqueous solution containing a surfactant dissolved therein, with stirring at high speed or with sonication to disperse the added substances and provide fine particles. However, in this emulsification method, a step for removing water is required for providing the fine particles in a powdered form, and the step gives variously restrictions to the process. Further, when using an organic solvent to dissolve the poorly water-soluble substance, there always has been a concern for residual toxic organic solvent.
US Patent No. 2004/0067251 A1 discloses a method for preparing fine particles by dissolving active ingredients into an organic solvent and spraying the resulted solution to an aqueous solution containing a surfactant dissolved therein. The invention involves the use of an organic solvent, and requires a drying process for removing the water used, to provide the particles as a powdered form, since the resulted particles are present in aqueous phase. During the drying process, the coagulation of the particles is likely to be occurred, hence the coagulated particles are hardly redispersed with maintaining the particle size to a nanoscale.
Recently, many attempts have been made to use a supercritical fluid in the amorphous or nanoscale particle preparation. Supercritical fluid is a fluid existing in liquid form at a temperature higher than its critical temperature and under pressure higher than its critical pressure. Commonly used supercritical fluid is carbon dioxide. As one of techniques involving the use of supercritical fluids in a nanoparticle preparation, the rapid expansion of a supercritical solution (hereinafter, RESS) is known from the following literatures: Tom et al. Biotechnol. Prog. 7(5):403-411. (1991); U.S. Pat. No. 6,316,030 B1; U.S. Pat. No. 6,352,737 B1; and U.S. Pat. No. 6,368,620 B2. According to RESS, an object solute is firstly dissolved in a supercritical fluid, and then the supercritical solution is rapidly sprayed into a relatively low-pressure condition via nozzle. Then, the density of the supercritical fluid rapidly falls down. As a result, the ability of the supercritical fluid to solubilize the solute is also rapidly reduced, and the solutes are formed into very minute particles or crystallines.
Other techniques using a supercritical fluid include a gas-antisolvent recrystallization (hereinafter, GAS) (Debenedetti et al. J. Control. Release 24:27-44. (1993); WO 00/37169). The method comprises dissolving a therapeutic agent in a conventional organic solvent to prepare a solution and spraying the resulted solution into a supercritical fluid served as an antisolvent, through a nozzle. Then, the volume becomes rapidly expanded upon the contact between the solution and the supercritical fluid. As a result, the density and capacity of the solvent become so much lower to cause excessive supersaturation, hence the solutes form seeds or particles.
U.S. Pat. No. 6,630,121 describes a method for preparing fine particles by nebulizing a solution containing active ingredients to provide fine particles with the use of a supercritical fluid, and drying the resulted particles with a dry gas. The method can be used regardless of the solubility of the active ingredients to the supercritical fluid. WO 02/38127 A2 describes a method using SEDS (Solution Enhanced Dispersion by Supercritical fluids) technique for preparing fine particles of active ingredients and coating the resulted fine particles with an additive such as a polymer. Further, U.S. Pat. No. 6,596,206 B2 describes a technique of preparing fine particles of active ingredients by dissolving the active ingredients in an organic solvent and focusing acoustic energy to the resulted solution so that the solution can be ejected into a supercritical fluid as a form of fine particles.